Regarding the electrode-tissue interface, selective activation or inhibition of a specific fiber group is an ongoing challenge. Strategies include altering the shape or pattern of the electrical stimulus, using a multi-channel cuff electrode, and using a more invasive microelectrode array. Many investigators have demonstrated enhanced control of target neuron populations using microelectrode arrays that penetrate the nerve with needle-like probes (e.g., the Utah Array) or flatten the nerve onto an array of planar electrodes (e.g., the Flat Interface Nerve Electrode, or FINE). Since the recording/stimulating sites can be placed nearer the target neurons, selectivity and control is improved. The advantage of these alternative electrode configurations comes at the expense of invasiveness and increased risk of nerve damage. Furthermore, the success of these alternative electrode configurations is largely dictated by a priori knowledge of target fiber location(s) in the nerve, significant experience and perhaps a bit of luck. While an optimal solution is a noninvasive therapy, a therapy employing some variant of the cuff electrode is the next best thing.
While a cuff electrode is generally safer and less invasive than microelectrode arrays that penetrate or flatten the nerve, their current designs are not ideal for selective nerve stimulation or control. Cuff electrodes make circumferential electrical contact with a nerve trunk or branch. With this configuration, all axons in the nerve are exposed to the excitatory and/or inhibitory stimuli, more so at the periphery due to a closer proximity to the source of the energy. Since all axons are exposed to the stimulus, it logically follows that all neurons may be activated if a strong enough stimulus is provided (in terms of pulse duration and amplitude).
Some degree of control is provided based on the natural recruitment order of axons by size, proximity to the electrode and degree of myelination, but knowledge of the stimulus-response profiles of the respective fiber types is required if precision is needed. Stimulus-response profiles are not collected in most electrical nerve stimulation (ENS) applications, because they differ across patients, within the same patient over time, and require tedious stimulus-response measurements for each activation level of interest. Furthermore, the compound nerve action potential (CNAP) response magnitude is a function of the biology (e.g., neuron type, temperature and ion composition), electrode viability (e.g., increased impedance or thermal noise due to protein adsorption and glial encapsulation) and environmental influence (e.g., electrical noise and the effects of certain drugs or chemicals). An adaptive, closed-loop control system is needed to personalize the stimulation and resulting effect to each patient.
Regarding the approaches to control or study meurophysiology, Joseph Bergmans first introduced the principles and utility of measuring single motor axon activation thresholds. He showed that many of the inherent physiological properties of a single motor fiber is embodied in changes to its activation threshold. Generally speaking, an accurate estimate of the nodal membrane potential, which is largely a function of the voltage-gated receptor type, number and distribution, along with factors that influence their function, is inferred from changes in the nodal membrane activation threshold in response to experimental membrane polarization. The techniques developed by Bergmans were difficult to master, however, leaving his research at a standstill for several years. SA Raymond later introduced the “Threshold Hunter,” a closed-loop circuit that clamps the probably of activation to 50% by dynamically adjusting the stimulus pulse duration. This tool significantly simplified the activation threshold measurement process first introduced by Bergmans.
Hugh Bostock and David Burke later introduced the “Threshold Tracker,” a software tool that characterizes properties of the nodal membrane at the point of stimulation by processing measured changes in the activation threshold of a population of neurons within a nerve. The Threshold Tracker was designed to measure changes in motor neuron function due to “metabolic and toxic neuropathies”—factors that influence or degrade the integrity and function of the nodal membrane—but was later deemed suitable for the study of sensory neuron function. In contrast to the Threshold Hunter introduced by Raymond, the Threshold Tracker fixes pulse width and varies pulse amplitude to maintain a set level of nerve activation, as inferred from the magnitude of the evoked compound nerve or muscle action potential. The membrane properties of a particular neuron type are determined through activation changes brought about by various polarizing and hyperpolarizing stimuli paired with a stimulus pulse having a fixed duration and amplitude.
Vagus nerve stimulation (VNS) is a treatment alternative for many epileptic and depressed patients whose symptoms are not well managed with pharmaceutical therapy. Approximately 2-weeks after device implantation, a physician programs the pacemaker-like device to deliver intermittent pulses of current to the left cervical vagus nerve. The highest efficacy is typically observed after 1 year, but only after several minimally informed stimulus parameter adjustments. The efficacy of these treatments is far from optimal.
Over the course of weeks to months, a physician systematically tunes the stimulus until the patient and physician feel that the therapy is working with no adverse or intolerable side effects. If a bothersome side effect is encountered, the intensity of stimulation is decreased until the side effect disappears. These parameters are maintained until the next appointment. Major limitations beyond the subjective nature of this approach include 1) the risk of adaption or desensitization to the stimulus, which may make the therapy less effective over time (e.g., stimulus induced depression of neuronal excitability, or SIDNE), 2) the lack of feedback regarding the type and number of neurons that are activated when the therapy is effective, and 3) the risk of patient discomfort.
All ENS therapies use some form of a stimulus parameter-based dosing system. This is problematic, as stimulus parameters are poor predictors of therapeutic efficacy; each patient and nerve responds uniquely to the same strength of stimulation, and the relationship between stimulation and the degree of nerve activation changes over time. These factors limit treatment benefit and contribute to poorer efficacy on a shorter timescale. They also help to explain why the therapeutic mechanisms are not well understood despite decades of investigation. An objective, informed dosing system is required to improve the efficacy of ENS therapies and to further reduce the number and severity of side effects.